RESUMO
Treatment resistance, the major challenge in the management of advanced prostate cancer, is in part based on resistance to apoptosis. The Inhibitor of Apoptosis (IAP) family is thought to play key roles in survival and drug resistance of cancer via inhibition of apoptosis. Of the IAP family members, cIAP1, cIAP2, XIAP and survivin are known to be up-regulated in prostate cancer. BIRC6, a much less studied IAP member, was recently shown to be elevated in castration-resistant prostate cancer (CRPC). In the present study, we showed a correlation between elevated BIRC6 expression in clinical prostate cancer specimens and poor patient prognostic factors, as well as co-upregulation of certain IAP members. In view of this, we designed antisense oligonucleotides that simultaneously target BIRC6 and another co-upregulated IAP member (dASOs). Two dASOs, targeting BIRC6+cIAP1 and BIRC6+survivin, showed substantial inhibition of CRPC cells proliferation, exceeding that obtained with single BIRC6 targeting. The growth inhibition was associated with increased apoptosis, cell cycle arrest and suppression of NFkB activation. Moreover, treatment with both dASOs led to significantly lower viable tumor volume in vivo, without major host toxicity. This study shows that BIRC6-based dual IAP-targeting ASOs represent potential novel therapeutic agents against advanced prostate cancer.
Assuntos
Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/genética , Oligonucleotídeos Antissenso/farmacologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose/biossíntese , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Terapia de Alvo Molecular , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Oligonucleotídeos Antissenso/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Distribuição Aleatória , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Recent evidence suggested that prostate cancer stem/progenitor cells (CSC) are responsible for cancer initiation as well as disease progression. Unfortunately, conventional therapies are only effective in targeting the more differentiated cancer cells and spare the CSCs. Here, we report that PSP, an active component extracted from the mushroom Turkey tail (also known as Coriolus versicolor), is effective in targeting prostate CSCs. We found that treatment of the prostate cancer cell line PC-3 with PSP led to the down-regulation of CSC markers (CD133 and CD44) in a time and dose-dependent manner. Meanwhile, PSP treatment not only suppressed the ability of PC-3 cells to form prostaspheres under non-adherent culture conditions, but also inhibited their tumorigenicity in vivo, further proving that PSP can suppress prostate CSC properties. To investigate if the anti-CSC effect of PSP may lead to prostate cancer chemoprevention, transgenic mice (TgMAP) that spontaneously develop prostate tumors were orally fed with PSP for 20 weeks. Whereas 100% of the mice that fed with water only developed prostate tumors at the end of experiment, no tumors could be found in any of the mice fed with PSP, suggesting that PSP treatment can completely inhibit prostate tumor formation. Our results not only demonstrated the intriguing anti-CSC effect of PSP, but also revealed, for the first time, the surprising chemopreventive property of oral PSP consumption against prostate cancer.
Assuntos
Quimioprevenção/métodos , Sistemas de Liberação de Medicamentos/métodos , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/prevenção & controle , Proteoglicanas/farmacologia , Animais , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neoplasias da Próstata/patologia , Proteoglicanas/uso terapêutico , Resultado do TratamentoRESUMO
Studies have shown that the expression of inhibitor of differentiation (Id-1) is increased in bladder cancer and is associated with drug resistance. S-allylmercaptocysteine (SAMC), a water-soluble component of garlic, is known to have a potent therapeutic effect on human cancer. The aim of this study was to investigate whether Id-1 expression mediates SAMC-induced cell death in bladder cancer cells. After generating stable Id-1-expressing and si-Id-1 transfectants in various bladder cancer cell lines, cell sensitivity to SAMC was compared by colony formation and MTT assays. The results indicated that Id-1 overexpression reduced the positive effect of SAMC on cell survival, while the inactivation of Id-1 increased cellular susceptibility to SAMC. Using DAPI staining, the apoptosis of bladder cancer cells induced by SAMC was shown to be negatively regulated by Id-1 expression. The expression of apoptosis-related proteins analyzed by Western blotting further supported the negative role of Id-1 in SAMC-induced apoptosis. Furthermore, by wound closure and type I collagen invasion assays, the inhibitory effect of SAMC on the invasion and migration of bladder cancer cells was found to be associated with the down-regulation of Id-1. Our results demonstrated that SAMC-induced apoptosis is associated with the Id-1 pathway, and that the inactivation of Id-1 enhances the ability of SAMC to inhibit the survival, invasion and migration of bladder cancer cells. These findings may lead to the development of novel therapeutic strategies for the treatment of bladder cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cisteína/análogos & derivados , Alho/química , Proteína 1 Inibidora de Diferenciação/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cisteína/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Neoplasias da Bexiga Urinária/genéticaRESUMO
Emerging evidence supports that prostate cancer originates from a rare subpopulation of cells, namely prostate cancer stem cells (CSCs). Conventional therapies for prostate cancer are believed to mainly target the majority of differentiated tumor cells but spare CSCs, which may account for the subsequent disease relapse after treatment. Therefore, successful elimination of CSCs may be an effective strategy to achieve complete remission from this disease. Gamma-tocotrienols (γ-T3) is one of the vitamin-E constituents, which have been shown to have anticancer effects against a wide range of human cancers. Recently, we have reported that γ-T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel-induced apoptosis, suggesting that γ-T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that γ-T3 can downregulate the expression of prostate CSC markers (CD133/CD44) in androgen-independent prostate cancer cell lines (PC-3 and DU145), as evident from Western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by γ-T3 treatment. In addition, pretreatment of PC-3 cells with γ-T3 was found to suppress tumor initiation ability of the cells. More importantly, although CD133-enriched PC-3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to γ-T3 treatment as the CD133-depleted population. Our data suggest that γ-T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies.
